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Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes

Smith, Kieran ; Taylor, Guy S. ; Peeters, Wouter ; Walker, Mark ; Perazzolo, Simone ; Atabaki-Pasdar, Naeimeh LU orcid ; Bowden Davies, Kelly A. ; Karpe, Fredrik ; Hodson, Leanne and Stevenson, Emma J. , et al. (2024) In Diabetologia 67(11). p.2555-2567
Abstract

Aims/hypothesis: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. Methods: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide,... (More)

Aims/hypothesis: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. Methods: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model. Results: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min−1 m−2) and type 2 diabetes (1.4 ± 0.7 l min−1 m−2) groups compared with Lean-NGT (1.9 ± 0.5 l min−1 m−2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ −0.75 l min−1 m−2; p<0.001). Conclusions/interpretation: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted. Trial registration: ISRCTN17563146 and ISRCTN95281775 Graphical Abstract: (Figure presented.)

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type
Contribution to journal
publication status
published
subject
keywords
Glucagon, Insulin clearance, Insulin resistance, Obesity, Postprandial glycaemia, Type 2 diabetes
in
Diabetologia
volume
67
issue
11
pages
13 pages
publisher
Springer
external identifiers
  • scopus:85201216614
  • pmid:39138690
ISSN
0012-186X
DOI
10.1007/s00125-024-06249-7
language
English
LU publication?
yes
id
3e623554-a43f-47da-a6fa-33566efe214a
date added to LUP
2025-01-07 13:21:16
date last changed
2025-01-21 15:06:15
@article{3e623554-a43f-47da-a6fa-33566efe214a,
  abstract     = {{<p>Aims/hypothesis: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. Methods: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model. Results: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p&lt;0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p&lt;0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min<sup>−1</sup> m<sup>−2</sup>) and type 2 diabetes (1.4 ± 0.7 l min<sup>−1</sup> m<sup>−2</sup>) groups compared with Lean-NGT (1.9 ± 0.5 l min<sup>−1</sup> m<sup>−2</sup>; p&lt;0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R<sup>2</sup>=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ −0.75 l min<sup>−1</sup> m<sup>−2</sup>; p&lt;0.001). Conclusions/interpretation: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted. Trial registration: ISRCTN17563146 and ISRCTN95281775 Graphical Abstract: (Figure presented.)</p>}},
  author       = {{Smith, Kieran and Taylor, Guy S. and Peeters, Wouter and Walker, Mark and Perazzolo, Simone and Atabaki-Pasdar, Naeimeh and Bowden Davies, Kelly A. and Karpe, Fredrik and Hodson, Leanne and Stevenson, Emma J. and West, Daniel J.}},
  issn         = {{0012-186X}},
  keywords     = {{Glucagon; Insulin clearance; Insulin resistance; Obesity; Postprandial glycaemia; Type 2 diabetes}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2555--2567}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1007/s00125-024-06249-7}},
  doi          = {{10.1007/s00125-024-06249-7}},
  volume       = {{67}},
  year         = {{2024}},
}